Pathologic formation of the arterial intima is widely considered to be the major cause of vascular narrowing in atherosclerosis, restenosis injury, and hypertension. As a result of an extensive characterization of balloon injury to the rat carotid artery, we now know the identity of specific molecules that control the initial proliferative response of the injured vessel, called "first wave," and the molecules that control migration of smooth muscle cells into the intima, called "second wave." We know much less, however, about why cells continue to proliferate once the neointima is formed, called "third wave," or why neointimal cells over-respond to mitogenic stimuli, a process we call "restimulation." Our Specific Aims attempt to identify molecules that control third wave replication and restimulation. The angiotensin system is of special interest both in restimulation and in the first three waves. Moveover, the effects of angiotensin could provide an etiologic link between these studies in large vessels to the special problems of microvascular proliferation in response to hypertension. Our studies include an exploration of possible interrelationships of angiotensin to more traditional growth factors known to control the proliferative response in this model. We are also interested in the possibility that local expression of PDGF-A functions as an autocrine co-mitogen, and in the possibility that the pathology of the neointima depends on the other genes we have identified by differential hybridization. To approach these questions, we propose, among other efforts, to try to control levels of expression of these genes in the neointima. Finally, these same questions may be relevant to the proliferative responses seen in hypertensive microvasculature. We have developed a new model for this response and propose to extend our efforts to the microvascular level.